Dissolution liquid for drug in iontophoresis

ABSTRACT

A drug held or supported by an interface comprising a porous matrix is dissolved with a drug dissolution liquid containing a humectant, and the drug is transdermally delivered by iontophoresis. The humectant includes e.g. glycerin and other polyhydric alcohols, sugar alcohols, proline and other amino acids and acidic mucopolysaccharides. The concentration of the humectant may be about 1 to 50% by weight, and the concentration of proline or other amino acid or its salt may be about 1 to 30% by weight. The drug includes (1) a physiologically active peptide or protein with a molecular weight of 100 to 30,000 or (2) a nonpeptide physiologically active compound with a molecular weight of 100 to 1,000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a dissolution liquid for a drug iniontophoresis which is useful for dissolving a drug in an interface (askin contactor or patch) for iontophoresis and delivering the drugtransdermally, and a method for promoting transdermal or percutaneousabsorption of the drug with the use of the dissolution liquid.

2. Description of Related Art

Iontophoresis is a system for promoting or accelerating transdermalabsorption (endermic absorption) with the use of electricity as anexternal stimulus. The principle of such iontophoresis basically residesin promoting or enhancing transmittance of a drug molecule through askin barrier due to, in an electric field between an anode and a cathodeproduced by an electric current, moving force of a positively chargedmolecule from the anode to the cathode, and a moving force of anegatively charged molecule from the cathode to the anode [see Journalof Controlled Release, 18, 213-220 (1992); Advanced Drug DeliveryReview, 9, 119 (1992); and Pharmaceutical Research, 3, 318-326 (1986)].

Recent advances of synthetic technologies and genetic engineering insurepure and mass production of a naturally-occurring peptide or protein, ora peptide or protein in which the amino acid composition of thenaturally-occurring peptide or protein is changed, or achemically-modified derivative thereof. Therefore, application of thesepeptides or proteins as drugs (medicaments) have been desired. On theother hand, it has been recognized that various physiological activitiesare physiologically controlled by delicate and complicated in vivokinetics with advanced researches for these peptides or proteins.Therefore, a system capable of corresponding to a strict control ofadministration (dosage) of these peptides or proteins is required forexhibition of the maximum drug effect in a specific disease andminimizing a side effect (adverse reaction).

By way of illustration, a calcitonin has an activity of inhibiting(suppressing) decrease of the amount of a bone by means of inhibitingbone resorption, and hence is used for treatment (therapy) ofosteoporosis, Paget's disease or other diseases. Although an excessiveadministration of the calcitonin causes a side effect such as anorexia(inappetence), frequent administration (frequent dosage), that is,repeated administration of the calcitonin is required for promotingtherapeutic effects for the disease. Further, some peptides exhibitdifferent drug effects depending on a medication process. Takingparathyroid hormone as an example, it has been known that theparathyroid hormone has incompatible effects or activities ofdeossification activity and ossification promoting activity, and thedeossification activity is strongly exhibited when the hormone isadministered by intravenous injection at a slow rate, and ossificationpromoting activity is clearly expressed when the hormone is administeredby frequent hypodermic injections. Accordingly, when the parathyroidhormone is used as a therapeutical drug for osteoporosis in expectationof its ossification activity, a pharmaceutical preparation comprisingthe hormone should be not a sustained releasable preparation but apulse-releasable preparation.

However, such physiologically active peptide or protein is generallydecomposed by a digestive fluid or juice in a gastrointestinal tract(digestive tract) or hydrolyzed by a hydrolase present in the digestivetract wall, and hence absorption efficiency of the peptide or proteincan hardly be improved effectively. Therefore, sufficient drug effect ofsuch physiologically active peptide or protein is not expected by oraladministration, and it is usually administered by an injection.Administration as an injectable preparation, however, causes a greatpain to a patient and burdens him with a heavy load since suchinjectable preparation can not be administered by himself. Still more,when repeated and continuous administration is required such as in thecalcitonin or parathyroid hormone, the pain and burden of the patientare increased, particularly speaking.

In the field of pharmaceutical preparations, the iontophoresis isintensively researched as a new drug delivery system capable ofcorresponding to administration or delivery of such physiologicallyactive peptide or protein. That is, development of a pharmaceuticalpreparation comprising a drug hitherto administrable only as aninjection and being administrable by a patient himself with the use ofthe iontophoresis will provide a therapy at home. Further, an optionalabsorption pattern of a drug can be constructed by means of a precisecontrol of an electric voltage or current application time (period). Inparticular, when the iontophoresis is applied supplemental therapy(treatment) of an endogenous compound in consideration of circadianrhythm of a living body, more effective therapy with it is expected tobe realized.

In a drug delivery system (administration system) with the use of theiontophoresis having such advantages, an electrode for application of anelectric current, a membrane holding or supporting a drug (an interfaceas a skin contactor or patch) which is conductible to the electrode andcapable of making contact with a skin, and a reference electrode aregenerally employed. The drug supported by the drug-supporting membraneis dissolved with a drug dissolution liquid contained in a spacercapable of making contact with the drug-supporting membrane.

An interface for iontophoresis which comprises a drug-supportingmembrane and a spacer containing a drug dissolution liquid is in a smallsize and has a high drug absorptivity. Use of the above interface,however, moisture content in a surface to be made contact with the skinand in the drug-supporting membrane is decreased due to transpiration orevaporation of the drug dissolution liquid during the application of theelectric current, and hence electric conductivity (applicability ofelectric current) is deteriorated. Hence, the iontophoresis using aninterface having such construction does not provide a satisfactorilysufficient transdermal drug delivery (drug absorption) with a prolongedapplication of the interface. Therefore, suppression of thetranspiration of the dissolution liquid seems to ensure maintenance ofthe electric conductivity over a long period, and to provide sufficienttransdermal drug delivery by means of iontophoresis.

WO 93/25168 discloses inhibition of an initial burst of transdermalabsorption by using a transdermal absorbent (drug composition)containing a drug and 0.1 to 50% (v/v) of glycerin in a transdermal drugdelivery system. This literature describes that the form of the drugcomposition is gel, cream or others, and the drug composition maycomprise an adhesive for supporting the composition in a site to whichthe composition is applied.

WO 90/08571 discloses a drug layer of an interface for iontophoresis asproduced with the use of a hard porous material or a gel, and water or apolyhydric alcohol such as glycerin as a softening plasticizer.

WO 93/10163 discloses a preparation process of a hydrophilic gel whichcomprises irradiating an aqueous composition comprising a crosslinkablewater-soluble polymer such as a polyethylene oxide, about 1 to 40% byweight of a humectant such as glycerin or propylene glycol, and acrosslinking accelerator with a radiation. This literature alsodescribes an application of the hydrophilic gel to a patch or anelectrode assembly.

These literatures, however, fail to disclose the use of a polyhydricalcohol or an amino acid for inhibition of moisture in a dissolutionliquid in the iontophoresis. Further, the use of such drug composition,drug layer or hydrophilic gel for transdermal drug administration byiontophoresis may occasionally result in an increased skin irritationaccompanied with the application of an electric current.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide a drugdissolution liquid which is useful for inhibiting transpiration ofmoisture from the drug dissolution liquid and hence maintaining electricconductivity (applicability of an electric current) over a long periodof time.

It is another object of the invention to provide a drug dissolutionliquid which is advantageous for transdermal drug absorption with a highbioavailability and an excellent reproducibility.

A further object of the invention is to provide a drug dissolutionliquid which ensures mitigation of a skin irritation accompanied withapplication of an electric current in the iontophoresis.

It is yet another object of the invention to provide an interface foriontophoresis and a drug delivery system with the use of theabove-mentioned drug dissolution liquid.

A still further object of the invention is to provide a method forpromoting transdermal absorption of a drug which promotes transdermalabsorption of a drug held or supported by an interface with efficacy andcertainty.

The inventors of the present invention made intensive investigation toaccomplish the above objects and found that incorporation of a humectantinto a drug dissolution liquid in an interface for iontophoresis ensureslong-term maintenance of conductivity (applicability of an electriccurrent) and provides transdermal administration of a drug with aremarkably high bioavailability and excellent reproducibility. Thepresent invention has been accomplished on the basis of the abovefindings and further investigation.

Thus, (1) the drug dissolution liquid of the present invention is adissolution liquid for transdermal drug delivery by iontophoresis withthe use of an interface comprising a porous matrix holding or supportinga drug, which comprises a humectant. The humectant may include at leastone member selected from the group consisting of polyhydric alcohols,sugar alcohols, amino acids and acidic mucopolysaccharides. Thepolyhydric alcohol may for example be a polyhydric alcohol having 2 to 4hydroxyl groups per molecule, such as glycerin. The amino acid may be anamino acid having a nitrogen-containing heterocycle such as anonaromatic nitrogen-containing 5-membered heterocycle (e.g. proline,hydroxyproline). The concentration of the humectant may be selectedwithin an adequate range, and the content of the polyhydric alcohol maybe about 10 to 50% by weight, and the concentration of the amino acidmay be about 1 to 30% by weight, typically speaking.

The drug (medicament or medicine) includes physiologically activepeptides or proteins, or non-peptide physiologically active compounds.

The present invention also discloses (2) an interface for iontophoresiswhich comprises a porous matrix holding or supporting a drug, and ahumectant, (3) a transdermal drug delivery (absorption) system which isprovided with an interface capable of making contact with a skin andcomprising a matrix holding or supporting a drug, a dissolution liquidfor dissolving the drug containing a humectant, and a supply means forsupplying the dissolution liquid to the interface for transdermaldelivery of the drug dissolved with the dissolution liquid by means ofiontophoresis. The matrix in the interface and the system may be anon-gel and porous matrix in the form of a sheet. The humectant may beheld or supported at least in an area or region to which an electriccurrent can be applied.

Further, the invention also discloses (4) an applicator which comprisesan electrode to which an electric voltage can be applied, and aninterface being conductible to the electrode, capable of making contactwith a skin and holding or supporting a drug, wherein the applicator iscapable of supplied with an aqueous solution containing a humectant fordissolution of the drug.

The present invention is useful as (5) a method for promotingtransdermal absorption of a drug by an interface for iontophoresis whichcomprises holding or supporting a drug and a humectant at least in anarea to which an electric current is applied.

It should be understood that the codes with respect to amino acids,peptides and so forth as used in the present specification are based oncodes according to IUPAC-IUB Commission on Biochemical Nomenclature, orconventional codes used in the field of art. When there are opticalisomers for an amino acid, the amino acid represents an L-form,otherwise specifically defined.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross sectional view illustrating an embodiment of anapplicator.

FIG. 2 is a graph showing changes of the concentration of hPTH (1→34) inthe serum (sometimes referred to briefly as serum hPTH (1→34)concentration) during the time course (time passage) in Example 1,Comparative Example 1 and Comparative Example 2.

FIG. 3 is a graph showing changes of the serum hPTH (1→34) concentrationduring the time course in Example 4 and Comparative Example 2.

FIG. 4 is a graph showing changes of the serum hPTH (1→34) concentrationduring the time course (time passage) in Example 5 and Example 6.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is now described in detail with referring to thedrawings where necessary.

The humectant contained in the drug dissolution liquid of the inventionis not particularly limited as far as being a substance which ensuresinhibition of transpiration of moisture from the drug dissolutionliquid, and provides maintenance or reservation of moisture (water) inthe surface to be made contact with a skin and in the drug-supporter(drug-holder) in the interface, and which does not adversely affect onthe skin. The humectant includes, for instance, (1) polyhydric alcohols,(2) sugar alcohols, (3) amino acids and (4) acidic mucopolysaccharides.These humectants may be used singly or in combination.

The polyhydric alcohol (1) includes, for example, glycerin, ethyleneglycol, propylene glycol, 1,3-butylene glycol, pentaerythritol,polyethylene glycol, adducts in which ethylene oxide is added to thesepolyhydric alcohols (e.g. dioxyethylene glycol, trioxyethylene glycol,polyoxyethylene glycol, an ethylene oxide-propylene oxide copolymer, aglycerin-ethylene oxide adduct, a penta-erythritol-ethylene oxideadduct, etc.). Such polyhydric alcohols can be employed independently orin combination. Preferred examples of the polyhydric alcohol includepolyhydric alcohols each having 2 to 4 hydroxyl group per molecule, inparticular glycerin.

As the sugar alcohol (2), there may be mentioned for example xylitol andother pentitol, sorbitol, mannitol, galactitol and other hexitol. Thesesugar alcohols may also be used singly or in combination.

Examples of the amino acid (3) include (i) an amino acid constituting aprotein, (ii) a naturally-occurring amino acid derived or obtained as ametabolite of a microorganism, or an animal or plant component, and(iii) an amino acid obtained by organic synthesis.

(i) The amino acid constituting a protein includes glycine, alanine,valine, leucine, isoleucine and other aliphatic monoaminomonocarboxylicacids; serine, threonine and other aliphatic hydroxyamino acids,aspartic acid, glutamic acid and other acidic amino acids; asparagine,glutamine and other acidic amino acid amides; phenylalanine, tyrosine,tryptophane and other aromatic amino acids; proline, hydroxyproline andother amino acids each having pyrrolidine ring; pyroglutamic acid(pyrrolidone-carboxylic acid) and other amino acids each havingpyrrolidone ring; arginine, lysine, histidine and other basic aminoacids; methionine, cystine, cysteine and other sulfur-containing aminoacids, for instance. Such amino acids may be employed independently orin combination.

(ii) As the naturally-occurring amino acid derived or obtained as ametabolite of a microorganism or an animal or plant component, there maybe mentioned, for example, L-α-aminobutyric acid, γ-aminobutyric acid,β-amino-isobutyric acid, β-alanine, homoserine, α-methyl-D-serine,O-carbamyl-D-serine, δ-hydroxy-γ-oxo-norvaline and other aliphaticmonoaminomonocarboxylic acids; L-α-aminoadipic acid, L-β-aminoadipicacid, L-theanine, L-γ-methylene-glutamic acid, L-γ-methylglutamic acidand other monoaminodicarboxylic acids; L-ornithine, β-ly-sine,α,β-diaminopropionic acid, L-α,γ-diaminobutyric acid and otherdiaminomonocarboxylic acids; diaminopimeric acid and otherdiaminodicarboxylic acids; cysteic acid and other sulfonicacid-containing monoaminomonocarboxylic acids; taurine and othersulfonic acid-containing amino acids; kynurenine,3,4-dioxyphenyl-L-alanine and other aromatic amino acids;2,3-dicarboxyaziridine, [S]-2-amino-3-(isoxazolin-5-on-4-yl)-propionicacid, anticapsin and other heterocyclic amino acids; L-4-oxalysine,L-4-oxolysine, [3R,5R]-3,6-diamino-5-hydroxyhexanoic acid and otherbasic amino acids; lanthionine, S-methyl-L-cysteine and othersulfur-containing amino acids; pipecolic acid, azetidine-2-carboxylicacid, [1R,2S]-2-amino-cyclopentan-1-carboxylic acid and other cyclicamino acids; citrulline, alanosine, azaserine and other specificfunctional group-substituted amino acids and so forth.

Examples of (iii) the amino acid obtained by organic synthesis includetrimethylglycine, 6-aminohexanoic acid, 8-aminooctanoic acid,12-aminododecanoic acid and other aliphatic aminocarboxylic acids,4-aminobenzoic acid, 4-(aminomethyl)benzoic acid,4-(N-(carboxymethyl)aminomethyl)benzoic acid and other aromaticaminocarboxylic acids.

The amino acid may be used in the form of a salt. The salt of the aminoacid includes, for example, a salt with a base [e.g. ammonia, alkalimetals (e.g. sodium, potassium) and other inorganic basis, andtrimethylamine, triethylamine and other organic basis], and a salt withan acid [hydrochloric acid, sulfuric acid, nitric acid, phosphoric acidand other inorganic acids, and acetic acid, propionic acid,p-toluenesulfonic acid and other organic acids].

Preferred amino acid includes amino acids each having anitrogen-containing heterocycle (e.g. proline, hydroxyproline and otheramino acids having pyrrolidine ring, pyrrolidonecarboxylic acid,histidine, tryptophane and other amino acids constituting a protein) orsalts thereof, typically speaking. Among them, amino acids each havingnonaromatic nitrogen-containing 5-membered heterocycle (e.g. amino acidseach having pyrrolidine ring such as proline and hydroxyproline andpyrrolidonecarboxylic acid) or salts thereof can advantageously beemployed.

(4) The acidic mucopolysaccharide includes, for instance, hyaluronicacid, chondroitin sulfate, and salts thereof [e.g. salts with alkalimetals (e.g. sodium, potassium)].

Among these humectants, polyhydric alcohols (in particular glycerin) andamino acids or salts thereof (in especial, proline and other amino acidseach having a nitrogen-containing heterocycle) may preferably be used.The use of the amino acid (in particular, proline and other amino acidseach having a nitrogen-containing heterocycle) or its salt ensuresremarkable mitigation of skin irritation accompanied with an electriccurrent application, and provides an increased quantity of appliedelectricity in an application of an electric current succeeding to thefirst application of current in a case that transdermal absorption isconducted in plural times at periodic intervals, and hence ensures animproved transdermal absorptivity.

The content of the humectant in the drug dissolution liquid comprisingan aqueous solution may be selected from a suitable range, according tothe species of the humectant, which ensures suppression of transpirationof moisture from the drug dissolution liquid and reserves the moistureon the surface of the skin and in the drug-supporter (drug-holder). Thecontent of the humectant is, for example, about 1 to 90% by weight,preferably about 1 to 80% by weight, and more preferably about 1 to 50%by weight based on the amount of the drug dissolution liquid. Amongthem, the amino acid and its salt ensures a high retention of moistureeven used in a small amount. In more concretely, when the humectant is apolyhydric alcohol such as glycerin, the content of the humectant in thedrug dissolution liquid is, for instance, about 5 to 50% by weight (e.g.about 10 to 50% by weight), and preferably about 20 to 40% by weight.When the humectant is the amino acid or its salt, the proportion of thehumectant in the drug dissolution liquid is about 1 to 30% by weight,preferably about 5 to 25% by weight, and more preferably about 10 to 20%by weight, generally speaking.

As the drug-support (drug-supporter, drug-holder, matrix) constitutingan interface for iontophoresis, use may be made of non-gel member(hereinafter may simply be referred to as "porous body") which iscapable of making contact with a skin, holding (retaining) or supportinga drug, and has a porous or capillary structure through which the drugcan be permeated. Such porous body includes organic porous bodies (e.g.fibrous aggregates made from cellulose and other naturally-occurringfibers, a cellulose acetate and other semisynthetic fibers,polyethylene, polypropylene, nylon, polyester and other syntheticfibers, paper and other sheets, a woven or nonwoven fabric and otherfabrics, a porous polypropylene, a porous polystyrene, a porouspoly(methyl methacrylate), a porous nylon, a porous polysulfone, aporous fluororesin and other porous synthetic resins).

The configuration or shape of the porous body is not particularlyrestricted, and the porous body may practically be in the form of asheet. The thickness of the sheet-like porous body can liberally beselected according to the retaining (holding) amount of the drug, and isfor example about 1 to 500 μm, and preferably about 10 to 200 μm. Theporous body may be a unde-formable body, but it may practically haveflexibility.

The area of the sheet-like porous body may suitably be selected from arange depending on the holding amount of the drug, and is about 1 to 10cm² and preferably about 2 to 8 cm², for instance.

The pore size of the sheet-like porous body may be liberally selectedwithin a range not interfering with the holding amount and releasabilityof the drug, and the mean pore size is, for example, about 0.01 to 20μm, preferably about 0.1 to 20 μm (e.g. about 0.2 to 20 μm) andpractically about 1 to 10 μm.

The application of the interface comprising a non-gel porous bodyholding or supporting a drug to a surface to make contact with a skin,the drug can be absorbed transdermally with high effectiveness andreproducibility through the matrix (porous body) by dissolving the drugwith the drug dissolution liquid.

The drug to be administered through the interface is not particularlylimited as far as being transdermally or percutaneously absorbable andbeing water-soluble, and various physiologically active peptides orproteins or nucleic acids, or non-peptide physiologically activecompounds of a low molecular weight can be employed. The molecularweight of the physiologically active peptide or protein or nucleic acidis, for instance, about 100 to 30,000, preferably about 200 to 20,000,more preferably about 500 to 10,000 and practically about 500 to 8,000).The molecular weight of the non-peptide physiologically active compoundwith a low molecular weight is not greater than about 1,000 (e.g. about100 to 1,000).

As the physiologically active peptide, there may be mentioned, forexample, the following peptides: Luteinizing hormone-releasing hormone(LH-RH), derivatives each having a similar function or activity toLH-RH, such as nafarelin and a polypeptide shown by the followingformula (I):

    (Pyr) Glu-R.sup.1 -Trp-Ser-R.sup.2 -R.sup.3 -R.sup.4 -Arg-Pro-R.sup.5(I)

wherein R¹ represents His, Tyr, Trp or p-NH₂ -Phe, R² represents Tyr orPhe, R³ indicates Gly or a D-amino acid residue, R⁴ denotes Leu, Ile orNle, R⁵ represents Gly-NH--R⁶, where R⁶ denotes a hydrogen atom or alower alkyl group which may have a hydroxyl group, or NH--R⁶, where R⁶has the same meaning as above, or a salt thereof [see U.S. Pat. No.3,853,837, U.S. Pat. No. 4,008,209, U.S. Pat. No. 3,972,859, BritishPatent No. 1423083, Proceedings of the National Academy of Science, 78,6509-6512 (1981)].

As examples of the D-amino acid residue shown by R³ in the formula (I),there may be mentioned α-D-amino acid having 9 carbon atoms or less(e.g. D-Leu, Ile, Nle, Val, Nval, Abu, Phe, Phg, Ser, Thr, Met, Ala,Trp, α-Aibu). These amino acids may have a protective group (e.g.t-butyl, t-butoxy or t-butoxycarbonyl group). The lower alkyl groupshown by R⁶ includes, for example, alkyl groups each having about 1 to 6carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl and t-butylgroups).

Incidentally, a salt (e.g. a salt with an acid) or metallic complexcompound of the peptide shown by the formula (I) can also be used in thesimilar manner as the peptide of the formula (I).

Among the polypeptides shown by the formula (I), a polypeptide (TAP-144)wherein R¹ =His, R² =Tyr, R³ =D-Leu, R⁴ =Leu and R⁵ =NHCH₂ --CH₃ ispreferably employed.

LH-RH antagonists such as a polypeptide shown by the following formula(II):

    N-α-t-butoxycarbonyl-O-benzyl-Ser-Trp-Ser-Tyr-X.sub.1 -Leu-Arg-Pro-GlyNH.sub.2                                  (II)

wherein X₁ represents D-Ser or D-Trp, or a salt thereof [see U.S. Pat.Nos. 4,086,219, 4,124,577, 4,253,997, and 4,317,815].

Snake poison (venom) peptides each having antagonistic activity againstGPIIb/IIIa, such as barbourin, peptides having Arg-Gly-Asp sequence,such as Arg-Gly-Asp-Ser, Gly-Arg-Gly-Asp-Ser-Pro, SK&F-106760(cyclo-S,S-[AcCys(N.sup.α -methyl)Arg-Gly-D-Asn-penicillamine]-NH₂), andother peptide-like compounds having a similar function or activity, suchas(S)-4-[(4-amidinobenzoyl)glycyl]-3-methoxy-carbonylmethyl-2-oxopiperazine-1-aceticacid,(S)-4-(4-guanidinobenzoylamino)acetyl-3-[3-(4-guanidinobenzoylamino)]propyl-2-oxopiperazine-1-aceticacid hydrochloride, MK-383(2-S-(n-butylsulfonylamino)-3-[4-(N-piperidin-4-yl)butyloxyphenyl)]-propionicacid-HCl), L-700462(L-Tyr-N-(butylsulfonyl)-O-[4-(piperidinyl)butyl]mono-hydrochloride),SC-56484 (ethyl[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxybutyl]amino-4-pentinoate),Ro-44-9883 ([1-[N-(p-amidinophenyl)-L-Tyr]-4-piperidinyl]acetic acid),DMP728 (cyclic[D-2-aminobutylyl-N-2-methyl-L-Arg-Gly-L-Asp-3-aminomethyl-benzoicacid]methanesulfonate.

Insulin; somatostatin, somatostatin derivatives, such as a polypeptideshown by the following formula (III): ##STR1## wherein Y representsD-Ala, D-Ser or D-Val, Z represents Asn or Ala, or a salt thereof [seeU.S. Pat. Nos. 4,087,390, 4,093,574, 4,100,117 and 4,253,998], growthhormone, growth hormone-releasing hormone; prolactin;adrenocorticotropic hormone (ACTH); melanocyte-stimulating hormone(MSH); thyroid stimulating hormone-releasing hormone (TRH), andderivatives thereof, such as a compound shown by the following formula(IV): ##STR2## wherein X^(a) represents a 4- to 6-membered heterocyclicgroup, Y^(a) denotes imidazol-4-yl or 4-hydroxylphenyl group, Z^(a)represents CH₂ or S, R^(1a) and R^(2a) independently represent ahydrogen atom or a lower alkyl group, and R^(3a) represents a hydrogenatom or an optionally substituted aralkyl group, or a salt thereof [seeJapanese Patent Application Laid-open No. 121273/1975 (JP-A-50-121273),Japanese Patent Application Laid-open No. 116465/1977 (JP-A-52-116465)].

Thyroid stimulating hormone (TSH); luteinizing hormone (LH);follicle-stimulating hormone (FSH); parathyroid hormone (PTH),derivatives each having a similar function or activity to theparathyroid hormone, such as a peptide shown by the following formula(V)

    R.sup.1b -Val-Ser-Glu-Leu-R.sup.2b -His-Asn-R.sup.3b -R.sup.4b -R.sup.5b -His-Leu-Asn-Ser-R.sup.6b -R.sup.7b -Arg-R.sup.8b -Glu-R.sup.9b -Leu-R.sup.10b -R.sup.11b -R.sup.12b -Leu-Gln-Asp-Val-His-Asn-R.sup.13b(V)

wherein R^(1b) represents Ser or Aib, R^(2b) represents Met or anaturally-occurring fat-soluble amino acid, R^(3b) denotes Leu, Ser, Lysor an aromatic amino acid, R^(4b) represents Gly or a D-amino acid,R^(5b) denotes Lys or Leu, R^(6b) represents Met or anaturally-occurring fat-soluble amino acid, R^(7b) denotes Glu or abasic amino acid, R^(8b) represents Val or a basic amino acid, R^(9b)represents Trp or 2-(1,3-dithiolan-2-yl)Tyr, R^(10b) denotes Arg or His,R^(11b) represents Lys or His, R^(12b) denotes Lys, Gln or Leu, andR^(13b) represents Phe or Phe-NH₂, or a salt thereof [see JapanesePatent Application Laid-open No. 32696/1993 (JP-A-5-32696), JapanesePatent Application Laid-open No. 247034/1992 (JP-A-4-247034),EP-A-510662, EP-A-477885, EP-A-539491], a peptide fragment of theN-terminus (1→34-position) of a human PTH (hereinafter referred to ashPTH (1→34) [G. W. Tregear et al., Endocrinology, 93, 1349-1353 (1973)];vasopressin, vasopressin derivatives {desmopressin [see Journal ofSociety of Endocrinology, Japan, 54, No. 5, 676-691 (1978)]}.

Oxytocin; calcitonin, derivatives each having a similar function tocalcitonin, such as a compound shown by the following formula (VI):##STR3## wherein X^(b) represents 2-aminosberic acid, or a salt thereof[Endocrinology, 1992, 131/6 (2885-2890)]; glucagon; gastrins; secretin;pancreozymin; cholecystokinin; angiotensin; human placental lactogen;human chorionic gonadotropin (HCG).

Enkephalin, enkephalin derivatives, such as a peptide shown by thefollowing formula (VII): ##STR4## wherein R^(1c) and R^(3c) respectivelyrepresent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,R^(2c) represents a hydrogen atom or a residue of a D-α-amino acid,R^(4c) denotes a hydrogen atom or an optionally substituted aliphaticacyl group having 1 to 8 carbon atoms, or a salt thereof (see U.S. Pat.No. 4,277,394, European Patent Application Laid-open No. 31567(EP-A-31567)) and other oligopeptides and endorphins.

Kyotorphine; interferons (α-, β-, γ-interferons); interleukins (e.g.interleukins I to XI); tuftsin; thymopoietin; thymostimulin; thymushumoral factor (THF); factor of thymus in serum (FTS) and theirderivatives, such as a peptide shown by the following formula (VIII):

    PGlu-X.sup.d -Lys-Ser-Gln-Y.sup.d -Z.sup.d -Ser-Asn-OH     (VIII)

wherein X^(d) represents L- or D-Ala, Y^(d) and Z^(d) independentlyrepresent Gly or a D-amino acid residue having 3 to 9 carbon atoms, or asalt thereof (see U.S. Pat. No. 4,229,438); and other thymus hormones[e.g. thymocin α₁ and β4, thymic factor X, etc. "Journal of ClinicalExperimental Medicine (IGAKU NO AYUMI)" 125, No. 10, 835-843 (1983)].

Tumor necrosis factor (TNF); colony stimulating factor (CSF); motilin;dynorphin; bombesin; neurotensin; cerulein; bradykinin; urokinase;asparaginase; kallikrein; substance P; nerve growth factor; factor VIIIand factor IX of blood coagulation factors; lysozyme chloride; polymyxinB; colistin; gramicidin; bacitracin; protein synthesis-stimulatingpeptide (British Patent No. 8232082); gastric inhibitory polypeptide(GIP); vasoactive intestinal polypeptide (VIP); platelet-derived growthfactor (PDGF); growth hormone-releasing factor (GRF, somatoclinine,etc.); born morphogenetic protein (BMP); epithelium growth factor (EGF);preprocortistatin (Nature, 381, 242-245 (1996)), erythropoietin and soon.

These physiologically active peptides may be human peptides, or peptidesderived from other animals such as bovines, swine, chickens, salmon, eeland so forth. Further, the peptide may be a chimera of a human peptideand a peptide derived from the above animal, or an active derivative inwhich a part of the structure of the peptide has been changed. By way ofan example, the insulin may be an insulin derived from a swine. As tothe calcitonin, use may be made of a calcitonin derived from a swine, achicken, salmon, or eel, or a peptide which is a chimera of a human andsalmon and is shown by the following formula (IX) [Endocrinology, 1992,131/6 (2885-2890)]:

    Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro       (IX)

Preferred examples of the drug include physiologically active peptidesand their derivatives, such as a calcitonin, adrenocorticotropichormone, parathyroid hormone (PTH), hPTH (1→34), insulins, secretin,oxytocin, angiotensin, β-endorphin, glucagon, vasopressin, somatostatin,gastrins, luteinizing hormone-releasing hormone, enkephalins,neurotensin, atrial natriuretic peptide, growth hormone, growthhormone-releasing hormone, bradykinin, substance P, dynorphin, thyroidstimulating hormone, prolactin, interferons, interleukins, GCSF,glutathioperoxidase, superoxide dismutase, desmopressin, somatomedin,endothelin, and their salts. Further, nucleic acids, nucleo-tides andvarious antigenic proteins may also be employed.

The salt of the physiologically active peptide or its derivativeincludes, for instance, a salt with an inorganic acid such ashydrochloric acid, sulfuric acid, hydrobromic acid and phosphoric acid;a salt with an organic acid such as formic acid, acetic acid, propionicacid, glycolic acid, oxalic acid, succinic acid, tartaric acid, citricacid, benzenesulfonic acid and p-toluenesulfonic acid; a complex saltwith an inorganic compound such as calcium and magnesium.

The nonpeptide physiologically active compound includes compounds eachhaving a molecular weight of about 1,000 or less and havingpharmacological activity. The species of the nonpeptide physiologicallyactive compound is not particularly limited, and as the compound, theremay be mentioned for example antibiotics, antimycosis (antifungaldrugs), hypolipidermic drugs, circulatory drugs, vasoconstrictors,antiplatelet drugs, antitumor drugs, antipyretic, analgesic and/orantiinflammatory agents, antitussive-expectorant agents, sedatives,muscle relaxants, antiepileptic drugs, antiulcer drugs, antidepressantagents, antiallergic agents, cardiotonics, antiarrhythmic agents,vasodilators, hypotensive-diuretic agents, drugs for diabetes,anticoagulants, hemostatic agents, antituberculosis drugs, hormones,narcotic antagonists, bone resorption-inhibitory agents, osteogeneticpromoting agents, angiogenesis inhibitors and so forth.

The antibiotic includes, for instance, gentamycin, lividomycin,sisomycin, tetracycline hydrochloride, ampicillin, cefalothin, cefotiam,cefazolin, tienamycin, sulfazecin and so on.

The antifungal agent includes, for example,2-[(1R,2R)-2-(2,4-difluorophenyl-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone,1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinoneand the like.

Examples of the vasoconstrictors include prostaglandin E₂ andprostaglandin F.

Examples of the hypolipidermic drug (antihyperlipidermic drug) inlcudeparavastatin and simvastatin. The circulatory drug inlcuds delaprilhydrochloride, for instance.

As the antiplatelet drug, there may be mentioned, for example,ticlopidine, cilostazol, limaprostat, aspirin and the like.

The antitumor drug (antineoplastic agent) includes, for instance,bleomycin hydrochloride, actinomycin-D, mitomycin-C, adriamycin andfluorouracil.

As examples of the antipyretic, analgesic and/or antiinflammatory agent,there may be mentioned sodium salicylate, sulpyrine, indomethacinsodium, hydromorphone, morphine hydrochloride, fentanyl, buprenorphineand so forth.

The antitussive/expectorant agent includes, for example, ephedrinehydrochloride, codeine phosphate and picoperidamine hydrochloride.

As the sedative, there may be mentioned chlorpromazine hydrochloride,and atropine sulfate, for instance. Examples of the muscle relaxant arepridinol methanesulfonate, tubocurarine chloride and so on.

As the antiepileptic agent, there may be mentioned for instancephenytoin sodium, ethosuximide and so forth. The antiulcer drugincludes, for example, metoclopramide. As the antidepressant, there maybe mentioned for instance imipramine and phenelzine sulfate.

Examples of the antiallergic drug are diphenhydramine hydrochloride,tripelennamine hydrochloride, clemizole hydrochloride and the like.

As the cardiotonic, there may be mentioned trans-π-oxocamphor andtheophyllol, for example. The antiarrhythmic agent includes, forinstance, propranolol hydrochloride and oxprenolol hydrochloride.Examples of the vasodilator include oxyfedrine hydrochloride, tolazolinehydrochloride, bamethan sulfate and so forth. The hypotensive-diureticagent includes, for instance, pentolinium, hexamethonium bromide and soon.

Examples of the antidiabetic agent (hypoglycemic drug) include glymidinesodium, glipizide, metformin, pioglitazone, Troglitazone and the like.As the anticoagulant, use may be made of sodium citrate, for example.

The hemostatic includes menadione sodium bisulfite, acetomenaphtone andtranexamic acid, typically speaking. As the antituberculosis drug, theremay be mentioned, for example, isoniazid and ethambutol.

Examples of the hormone drug include β-estradiol, testosterone,prednisolone succinate, dexamethasone sodium sulfate, methimazole and soforth. The narcotic antagonist includes, for example, levalorphantartrate and nalorphine hydrochloride. As example of the bone resorptioninhibitory drug, there may be mentioned (sulfur-containingalkyl)aminomethylene bisphophoate.

Examples of the osteogenetic promoting agents include(2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide.

As the angiogenesis inhibitor, there may be mentioned, for instance, avascularization inhibitory steroid [see Science 221, 719 (1983)],fumagillol derivatives, [e.g. 0-monochloroacetyl-carbamoylfumagillol,O-dichloroacetylcarbamoylfumagillol (see EP-A-357061, EP-A-359036,EP-A-386667 and EP-A-4152943)].

The drug may be held or supported by the drug holder (porous body) bydissolving the drug in a distilled water for injection, a physiologicalsaline for injection or the like to give an aqueous solution, andapplying the solution to the drug holder in a conventional manner suchas impregnation, spraying, application, dropwise-adding or the like, anddrying the resultant. When the drug is the physiologically activepeptide or protein, a dissacharide (e.g. trehalose, maltose, mannitoland inositol) may be added to the aqueous solution containing the drugfor improvement of stability of the drug in dry conditions. Theproportion of the dissacharide is, for example, about 0.1 to 10 mg/ml,and preferably about 1 to 5 mg/ml (e.g. about 1 to 4 mg/ml).

Long-term preservation of the drug held or supported by the matrix (drugholder or drug retainer) with maintaining activities of the drug can beeffected by storing the drug in dry condition. More concretely,preservation of the drug in dry condition may be conducted by, forinstance, a process which comprises efficiently drying the drug holderholding the drug, and packaging the drug holder with a film having asmall water permeability (e.g. an aluminum film) by vacuum sealingmethod. Further, in order to retain the dry condition with certainty,the drug holder supporting the drug may be vacuum-sealed and packagedtogether with a desiccating agent or dryer (e.g. a zeolite-baseddesiccator such as "SELAM" manufactured by Tokai Chemical Industries,Ltd., a silica gel-based desiccator, etc.). When the drug is to beoxidatively decomposed, an oxygen absorbent (e.g. "AGELESS" manufacturedby Mitsubishi Gas Chemical Co., Ltd.) may be incorporated into thepackage in addition to the desiccating agent.

The holding amount of the drug relative to the matrix (drug holder) mayonly be an effective amount according to the species of the drug,species of the drug holder, area or portion to be administered, and is,for example, about 0.1 to 100 μg, and preferably about 0.5 to 50 μg(e.g. about 1 to 50 μg) per 1 cm² of the sheet-like drug holder.

In the present invention, the interface for iontophoresis may becomposed of the porous matrix holding or supporting the drug asmentioned above, or it may be composed of the porous matrix holding orsupporting the drug, and the humectant held or supported by the porousmatrix.

Incidentally, the drug is not necessarily held by the sheet-like matrix(e.g. a holder in the form of a membrane), and a solution containing thedrug may be injected into the holder or neighborhood of the holder. Insuch a case, the interface may also be composed of the matrix and thehumectant held or supported by the matrix. The drug may be incorporatedinto the dissolution liquid, that is, the dissolution liquid may containthe humectant and the drug.

Furthermore, a suitable adsorption inhibitor may be incorporated intothe dissolution liquid for dissolving the drug in order to ensurefurther inhibition of loss of the physiologically active peptide orprotein due to adsorption. The adsorption inhibitor includes, forinstance, an albumin (e.g. a bovine serum albumin (BSA), a human serumalbumin (HSA) and other serum albumins), gelatin and other water solubleproteins; alkylbenzenesulfonic acid salts (e.g. a sodium salt) and otheranionic surfactants, a C₈₋₂₀ alkyltrimethylammonium chloride, a C₈₋₂₀alkyltrimethylammonium chloride, a C₈₋₂₀ alkylbenzyldimethylammoniumchloride (benzalkonium chloride, hereinafter sometimes referred to asBAC), a 4-C₁₋₁₀ alkylphenyloxyethoxyethylbenzyldi-methylammoniumchloride (e.g. benzethonium chloride) and other cationic surfactants,Tween 80 and other nonionic surfactants, and alkali metal salts (e.g.sodium chloride) and the like. The amount of the adsorption inhibitormay for example be about 0.00001 to 1% (w/w), preferably about 0.0001 to0.5% (w/w), and more preferably about 0.001 to 0.1% (w/w) based on theamount of the dissolution liquid. Further, an appropriate absorptionaccelerator (e.g. monoterpene, aliphatic monoglyceride, Azone(manufactured by Nelson), limonen, oleic acid, lauric acid, octanol) maybe incorporated into the drug dissolution liquid. The content of theabsorption accelerator is, for instance, about 0.1 to 80% (w/w),preferably about 0.5 to 50% (w/w), and more preferably about 1 to 30%(w/w) based on the amount of the dissolution liquid.

The interface composed of the drug holder (porous body) is useful fortransdermal drug delivery (endermic drug administration) byiontophoresis with the use of a variety of applicator which isapplicable to a skin. The applicator is provided with an electrode towhich an electric voltage is applicable, and an interface which isconductible to the electrode, capable of making contact with a skin, andholds or supports the drug. The applicator is capable of being suppliedwith an aqueous solution, for dissolving the drug, containing thehumctant. The transdermal drug delivery system of the inventioncomprises an interface composed of the matrix (in particular thesheet-like porous body), the humectant-containing dissolution liquid fordissolving the drug, and a supply means for supplying the dissolutionliquid to the interface. The drug dissolved with the dissolution liquidis transdermally or endermically absorbed by means of iontophoresis.FIG. 1 is a cross sectional view illustrating an embodiment of theapplicator comprising the interface.

The applicator shown in FIG. 1 is provided with a support (base member)4 having flexibility and being formed with an opening 9, and a container(reservoir) 3 disposed in a part corresponding to the opening 9. Thecontainer is provided with an electrode 1 such as a silver electrode,and accommodates electric conductor 2 such as an electric conductivenonwoven fabric or sponge containing water or an electric conductive gelsuch as a water-containing gel, poly(vinyl alcohol) (PVA) comprisingNaCl. The electric conductor 2 may comprise a porous sponge or nonwovenfabric containing an aqueous solution comprising a hydrophilic substancewith water retentivity. In the part of the under portion of the support4 corresponding to the opening 9 are disposed an ion exchange membrane5, the inner surface of which faces to the electric conductor 2, and aninterface 6 as laminated by means of an adhesive tape 7. The adhesivetape 7 is utilized for attaching the applicator to the skin. Theelectric conductor 2 of the container 3 is conductible to the electrode1 and capable of making contact with the ion exchange membrane 5 andinterface 6 through the opening 9. Further, an injection port 10 capableof injecting a liquid is formed between the ion exchange membrane 5 andthe interface 6.

When such an applicator is used in a case where the interface holds orsupports the drug, a nozzle tip of an injection tip 8 may be inserted tothe injection port 10 between the ion exchange membrane 5 and theinterface 6 to inject the drug dissolution liquid such as a distilledwater for injection containing the humectant. When the interface doesnot hold or support the drug, a solution containing the drug and thedrug dissolution liquid containing the humectant may be respectivelyinjected to the interface 6, and in a case that the interface holds orsupports both the drug and the humectant, the drug dissolution liquidsuch as a distilled water for injection may only be injected to theinterface 6.

The amount of the drug dissolution liquid to be injected may be selectedfrom a range according to the size of the applicator, the surface areaof the interface and the holding amount of the drug, and usually isabout 30 to 500 μl and preferably about 50 to 200 μl.

Incidentally, in the support of the applicator, a second container(reservoir) as a reservoir for reservation of a liquid for drugdissolution such as a distilled water for injection may be disposed inthe opening distant from the first container, and an interface may belaminated, through a nonwoven fabric disposed in the area from the firstcontainer toward the second container, on the outer surface of the ionexchange membrane. When such applicator is used, the second containermay be pierced by, for example inserting a needle through the secondcontainer and the support to form a pore in the support connecting tothe inside of the second container, so that the liquid for dissolutionof the drug or drug-containing solution is permeated to the nonwovenfabric for dissolution of the drug held by the interface or forsupplying the drug-containing solution to the interface.

The first and second containers can be formed by, for instancepolyethylene or other synthetic resins. As the ion exchange membrane,use may be made of various membranes each having ion exchangecapability, such as "AC220 Membrane" (trade name) manufactured by AsahiChemical Industries, Japan. As the nonwoven fabric, a variety ofnonwoven fabrics through which a liquid is permeable, such as "BenbergHalf" (trade name) manufactured by Asahi Chemical Industries, Japan, canbe used. As the adhesive tape, use may be made of a variety of adhesivetapes each having adhesive properties with respect to a skin, such as"Blenderm" (trade name) manufactured by 3M Pharmaceuticals, M.N.(Minnesota).

For the purpose of inhibiting or suppressing transpiration ordissipation of moisture not only from the interface but also from theskin, and hence improving electric conductivity by means of thehumectant in the drug dissolution liquid in the delivery process ortransdermal delivery system with the use of the above applicator, thedrug dissolution liquid is required to diffuse through the matrix (drugholder) to the skin. It is effective to hold or support the humectant atleast in an area to which the electric current is applied in order torestrain transpiration or dissipation of moisture and to administer thedrug effectively. In this system, transdermal absorption (delivery) ofthe drug by means of the interface for iontophoresis can be promoted byholding or supporting the drug and the humectant at least in an area ofthe interface to which electric current is applied. In particular, whenmoisture is supplemented by, for example, a single supply of thehumectant-containing dissolution liquid, and hence the humectant is heldor supported in the area to which the electric current is applied,electric conductivity can be maintained with inhibiting transpiration ordissipation of moisture over a long period. Therefore, when the drug isdelivered or administered by means of plural electric currentapplications, such a complicated operation is not required as to supplythe drug dissolution liquid such as a distilled water plural times inorder to supply the moisture in succeeding current application step.Especially, use of the amino acid or its salt as the humectant ensuresinhibition of transpiration or dissipation of the moisture even in asmall amount and mitigates skin irritation accompanied with the currentapplication, so that it is useful for transdermal drug delivery by meansof iontophoresis.

The transdermal delivery (endermic administration) of the drug by meansof iontophoresis can be effected by applying an electric current to theelectrode of the applicator and a reference electrode to pass anelectricity. As the electric current voltage, an alternating currentvoltage may be employed but use is practically made of a direct currentvoltage. As such direct current voltage, not only a continuous directcurrent voltage but also a depolarized direct current pulse voltage canbe utilized. Preferably, use may be made of an electric power supplywhich can apply a depolarizing pulse direct current voltage, inparticular, a square pulse direct current voltage. The frequency of thepulse direct current voltage may be selected within a range of, forexample, about 0.1 to 200 kHz, preferably about 1 to 100 kHz and morepreferably about 5 to 80 kHz. The ON/OFF ratio of the pulse directcurrent voltage is, for instance, about 1/100 to 20/1, preferably about1/50 to 15/1 and more preferably about 1/30 to 10/1. The applied voltagemay be selected from a range not injuring a skin of a living body andnot adversely affecting the transdermal absorption ratio, and is, forinstance, about 1 to 20 V, and preferably about 3 to 15 V. The currentapplication time is, for example in continuous application of thecurrent, not longer than 24 hours, preferably not longer than 12 hoursand in particular not longer than 6 hours.

The present invention, where the drug dissolution liquid containing thehumectant is used, provides inhibition of transpiration of the moisturefrom the drug dissolution liquid and hence ensures long-period retentionof electric conductivity in the drug delivery system with the use ofiontophoresis. Accordingly, the invention provides effective and certaintransdermal absorption of the drug held in the interface, and is usefulfor transdermal delivery of the drug with high bioavailability andexcellent reproducibility. Further, the use of the amino acid or itssalt as the humectant mitigates skin irritation accompanied withapplication of electric current, and hence is useful for transdermaldrug delivery by means of iontophoresis.

The following examples are intended to illustrate the present inventionin more detail, but should by no means limit the scope of the invention.

EXAMPLES Comparative Example 1

An abdominal skin of a male SD rat (7-week aged) was clipped with a hairclipper and treated with a shaver under pentobarbital-anesthetization,and was cleaned with an absorbent cotton containing a 70% aqueoussolution of ethanol for defatting and disinfection.

In the iontophoresis was used an applicator illustrated in FIG. 1. Thatis, the drug holder (Biodyne Plus Membrane, Nihon Pall Ltd., Japan; 2.5cm²) was previously dipped in a 10% (w/v) bovine serum albumin (BSA) anddried to hold or possess 40 μg of hPTH (1→34) per membrane in drycondition and thereby an interface for iontophoresis was obtained. Thisinterface was applied and fixed to the abdominal skin of the rat. Afterapplication of the interface to the skin, the dried drug was dissolvedby supplying 120 μl of a distilled water from an injection tip 8 to theinterface. The electric current application was effected by using apulse direct current electric voltage of a direct-current 12-V constantvoltage with a frequency of 40 kHz and an ON/OFF ratio of 3/7, andrepeating three times a combination of 15-minutes current applicationand 5-minute-non-current application. This current application patternwas repeated three times with an interval of 2 hours. After apredetermined time lapse, blood was took from jugular veins (cervicalvein) of the rat and centrifuged at a rate of 12,000 rpm for 10 minutesto give a serum sample. The concentration (pg/ml) of the hPTH (1→34) inthe serum was determined by radioimmunoassay method. The results areillustrated in FIG. 2. In FIG. 2, long narrow boxes in axis of abscissa(time) represent electric current application time.

Comparative Example 2

The hPTH (1→34) was transdermally administered in the same manner asComparative Example 1 using the same interface for iontophoresis,administration process, conditions of current application anddetermination method of serum hPTH (1→34) concentration, except that 60μl of a distilled water was supplied from the injection tip 8immediately before the second and third current application cyclesrespectively. The results are set forth in FIG. 2.

Example 1

The hPTH (1→34) was administered in the same interface foriontophoresis, administration process, conditions for currentapplication and determination method of the serum hPTH (1→34)concentration as Comparative Example 1 except that 120 μl of a 30% (w/w)glycerin aqueous solution in lieu of the distilled water was injectedonce after adhesion of the interface. The results are shown in FIG. 2.

As apparent from FIG. 2, in the single supply of the distilled water(Comparative Example 1), third peak corresponding to the numbers of thecurrent application cycles was not found, to the contrary, in the singlesupply of the 30% (w/w) glycerin aqueous solution (Example 1), threepeaks corresponding to the current application cycles were found,equaling to the three times-supply of the distilled water (ComparativeExample 2). The bioavailability (BA) was evaluated from the ratio of thearea under the serum hPTH concentration-time curve (AUC value) of thetested group relative to the AUC value obtained by intravenousadministration on same dose basis [actual intravenous dose, 2 μg/kg ofhPTH (1→34)]. The BA was 17.8%, 9.0% and 13.8% for Example 1,Comparative Example 1 and Comparative Example 2 respectively. Thus, thesingle supply of 30% (w/w) aqueous solution of glycerin provides anequal absorptivity to the three times supply of the distilled water.

Example 2

By conducting a single injection of 120 μl of a 10% (w/w) aqueoussolution of glycerin in lieu of the distilled water after application ofthe interface, the hPTH (1→34) was transdermally delivered in the samemanner as Comparative Example 1 employing the same interface foriontophoresis, administration process and conditions for currentapplication.

In the single supply of the 10% (w/w) aqueous solution of glycerin(Example 2), the bioavailability (BA) was 9.5%, as evaluated from theratio of the area under the serum hPTH concentration-time curve (AUCvalue) of the tested group relative to the AUC value obtained byintravenous administration on same dose basis [actual intravenous dose,2 μg/kg of hPTH (1→34)].

Example 3

Except that single injection of 120 μl of a 60% (w/w) aqueous solutionof glycerin in lieu of the distilled water was conducted afterapplication of the interface, the hPTH (1→34) was transdermallyadministered employing the same interface for iontophoresis,administration process and conditions of current application asComparative Example 1.

In the single supply of the 60% (w/w) aqueous solution of glycerin(Example 3), the bioavailability (BA) was 18.5%, as evaluated from theratio of the area under the serum hPTH concentration-time curve (AUCvalue) of the tested group relative to the AUC value obtained byintravenous administration on same dose basis [actual intravenous dose,2 μg/kg of hPTH (1→34)].

Example 4

The hPTH (1→34) was transdermally administered in the same interface foriontophoresis, administration process and conditions for currentapplication as Comparative Example 1, except that 120 μl of a 30% (w/w)aqueous solution of proline was once injected, instead of the distilledwater, after application of the interface by using the same interfacefor iontophoresis, administration process and conditions for currentapplication as Comparative Example 1. The results are illustrated inFIG. 3. The results of Comparative Example 2 are also shown in FIG. 3.In FIG. 3, narrow and long boxes in the axis of abscissa (time) denotecurrent application time (period).

As clearly shown in FIG. 3, similar blood concentration pattern toExample 1 was obtained by a single supply of the 30% (w/w) aqueoussolution of proline, and the bioavailability (BA) was 17.6% as evaluatedfrom the ratio of the area under the serum hPTH concentration-time curve(AUC value) of the tested group relative to the AUC value obtained byintravenous administration on same dose basis [actual intravenous dose,2 μg/kg of hPTH (1→34)].

Example 5

Except that 120 μl of a 10% (w/w) aqueous solution of proline in lieu ofthe 30% (w/w) aqueous solution of proline was injected after applicationof the interface, the hPTH (1→34) was transdermally administeredemploying the same interface for iontophoresis, administration processand conditions of current application as Example 4. The results are setforth in FIG. 4. As apparent from FIG. 4, the single supply of the 10%(w/w) aqueous solution of proline provide a similar pattern of the hPTH(1→34) in serum to Example 1, and BA was 17.8%.

Example 6

The hPTH (1→34) was transdermally administered by employing the sameinterface for iontophoresis, administration process and conditions ofcurrent application as Example 4, except that 120 μl of 10% (w/w)aqueous solution of sodium pyroglutamate was injected in lieu of the 30%(w/w) aqueous solution of proline after application of the interface.The results are shown in FIG. 4. As clearly illustrated in FIG. 4, asingle supply of the 10% (w/w) aqueous solution of sodium pyroglutamateresulted in a similar pattern of the hPTH (1→34) in blood to Example 1,and BA was 15.2%.

What is claimed is:
 1. A dissolution liquid for transdermal drugdelivery by iontophoresis with the use of an interface composed of aporous matrix holding or supporting a drug, wherein the dissolutionliquid comprises water and selected from the group consisting ofpolyhydric alcohols having 2 to 4 hydroxyl groups per molecule, sugaralcohols, amino acids and an amino acid as a humectant.
 2. A dissolutionliquid as claimed in claim 1, wherein the amino acid has anitrogen-containing heterocycle.
 3. A dissolution liquid as claimed inclaim 1, wherein the amino acid has a non-aromatic nitrogen-containing5-membered heterocycle.
 4. A dissolution liquid as claimed in claim 1,wherein the amino acid is proline or hydroxyproline.
 5. A dissolutionliquid as claimed in claim 1, wherein the concentration of the aminoacid is 1 to 30% by weight.
 6. A dissolution liquid as claimed in claim1, wherein the drug is (1) a physiologically active peptide or protein,or (2) a nonpeptide physiologically active compound.
 7. A dissolutionliquid as claimed in claim 1, wherein the drug is (1) a physiologicallyactive peptide or protein with a molecular weight of 100 to 30,000, or(2) a nonpeptide physiologically active compound with a molecular weightof 100 to 1,000.
 8. A dissolution liquid as claimed in claim 1, whereinthe dissolution liquid is a liquid for dissolving a physiologicallyactive peptide or protein with a molecular weight of 100 to 30,000 beingheld or supported by a matrix, and comprises an aqueous solutioncontaining an amino acid as a humectant in a proportion of 1 to 50% byweight.
 9. A dissolution liquid for transdermal drug delivery byiontophoresis with the use of an interface composed of a porous matrix,wherein the dissolution liquid comprises water, an amino acid as ahumectant and a drug.
 10. An interface for iontophoresis which comprisesa porous matrix holding or supporting a drug and the dissolution liquidas claimed in claim
 1. 11. A transdermal drug delivery system which isprovided with an interface capable of making contact with a skin andcomprising a matrix holding or supporting a drug, the dissolution liquidas claimed in claim 1, and a supply means for supplying the dissolutionliquid to the interface, wherein the drug dissolved with the dissolutionliquid is transdermally derived by means of iontophoresis.
 12. Atransdermal drug delivery system as claimed in claim 11, wherein thematrix is a porous nongel matrix in the form of a sheet.
 13. Atransdermal drug delivery system as claimed in claim 11, wherein theamino acid is held or supported at least in an area to which an electriccurrent is applied.
 14. An applicator comprising an electrode, to whichan electric voltage is applicable, and the interface as claimed in claim10 being conductible to the electrode, capable of making contact with askin.
 15. A method for promoting transdermal absorption of a drug bymeans of an interface for iontophoresis, which comprises holding orsupporting a drug and the dissolution liquid as claimed in claim 1 atleast in an area to which an electric current is applied.
 16. Atransdermal drug delivery process which comprises allowing an interfaceholding or supporting a drug to make contact with a skin, and dissolvingthe drug with the dissolution liquid as claim in claim 1.